RESUMEN
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (both p < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1-99) and tMDS (13 months; range 0-160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0-345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.
Asunto(s)
Leucemia Mieloide Aguda , Mieloma Múltiple , Síndromes Mielodisplásicos , Neoplasias Primarias Secundarias , Humanos , Cariotipificación , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/terapia , Neoplasias Primarias Secundarias/etiologíaRESUMEN
Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Células Madre Mesenquimatosas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/genética , Antígenos CD34/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Femenino , Hematopoyesis/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Jagged-1 , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogénesis/efectos de los fármacos , Fenotipo , Proteínas Serrate-Jagged , Transducción de Señal , Factor de Células Madre/genética , Factor de Células Madre/metabolismoRESUMEN
Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.
Asunto(s)
Células Madre Mesenquimatosas/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Diferenciación Celular , Proliferación Celular , Senescencia Celular , Análisis por Conglomerados , Ensayo de Unidades Formadoras de Colonias , Metilación de ADN , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Masculino , Células Madre Mesenquimatosas/citología , Persona de Mediana Edad , Osteogénesis/genética , FenotipoAsunto(s)
Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Recuento de Linfocitos , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Linfocitos T Reguladores , Antimetabolitos Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Humanos , Recurrencia , Terapia Recuperativa , Trasplante HomólogoRESUMEN
The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461-888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Trasplante de Células , Leucemia Mieloide Aguda/terapia , Linfocitos/citología , Síndromes Mielodisplásicos/terapia , Terapia Recuperativa , Trasplante de Células Madre , Adulto , Anciano , Terapia Combinada , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/cirugía , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/cirugía , Recurrencia , Trasplante HomólogoRESUMEN
In the current study, we evaluated a combination of tacrolimus and mycophenolate mofetil (MMF) as GvHD prophylaxis in 50 patients undergoing truly nonmyeloablative (NM; 90 mg/m(2) fludarabine, 2 Gy TBI) hematopoietic SCT (HSCT) from unrelated donors. Median patient age was 51 years (range, 25-67 years). After a median follow-up of 1123 days (range, 47-2729 days), 20 patients (40%) are alive and free from disease. The probabilities of 1-, 2- and 3-year survival were 57, 47 and 39%, respectively. Patients who achieved a remission before HSCT had a significantly better OS compared with those who had active disease (P=0.01). The incidences of grade II-IV and III-IV acute GvHD (aGvHD) were 54% (n=27) and 16% (n=8). Remarkably, using tacrolimus and MMF, the median onset of aGvHD occurred distinctly late on day +66 (range, 12-119 days). A total of 46 patients were evaluable for chronic GvHD (cGvHD). Out of these, 26 (56%) patients developed cGvHD, with 16 (34%) of them showing limited and 10 (21%) showing extensive disease. We conclude that the combination of tacrolimus and MMF as post transplant immunosuppression for patients receiving NM unrelated donor HSCT permits stable engraftment and effective prophylaxis for acute and cGvHD. In particular, the occurrence of severe early-onset aGvHD was attenuated.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Tacrolimus/administración & dosificación , Adulto , Anciano , Femenino , Enfermedades Hematológicas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Tacrolimus/uso terapéutico , Quimera por Trasplante , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Irradiación Corporal TotalRESUMEN
BACKGROUND: We retrospectively determined whether a 3-day short course of palifermin could reduce the toxicity of high-dose therapy (HDT) and autologous blood stem-cell transplantation (ASCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: Sixty-seven consecutive patients received 60 mug/kg palifermin for 3 days before HDT with melphalan 200 or 140 mg/m(2) for patients with renal failure (group A). Granulocyte colony-stimulating factor (G-CSF) was applied after ASCT. Data on haematopoietic reconstitution and toxicity were compared with two previously published patient groups from our institution who had received pegfilgrastim but not palifermin (group B, n = 21) and patients who had received neither palifermin nor G-CSF (group C, n = 21). RESULTS: In group A, patients with renal failure had a significantly higher risk for severe mucositis (64% versus 16%, P < 0.002). Patients with normal renal function who received palifermin experienced significantly less days of hospitalisation (P < 0.05) and less need for narcotic analgesia (P < 0.05), parenteral nutrition (P < 0.05) and erythrocyte transfusions (P < 0.05) in comparison with groups B and C. Time to haematopoietic reconstitution was not compromised by the use of palifermin. CONCLUSIONS: In conclusion, a short 3-day course of palifermin may be able to reduce the toxicity of HDT and ASCT in patients with MM. Patients with impaired renal function at the time of HDT need additional strategies to further reduce the incidence of severe mucositis.
Asunto(s)
Factor 7 de Crecimiento de Fibroblastos/uso terapéutico , Mucositis/prevención & control , Mieloma Múltiple/terapia , Recurrencia Local de Neoplasia/prevención & control , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Femenino , Filgrastim , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mucositis/etiología , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Cuidados Paliativos , Polietilenglicoles , Proteínas Recombinantes , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Patients with AML or myelodysplastic syndrome who relapse after allo-SCT have a poor prognosis. In the search for novel treatment strategies for these patients, we conducted a multicenter retrospective analysis and identified 22 patients treated with the DNA-methylation inhibitor 5-azacytidine (5-Aza). Patients received a median number of two cycles 5-Aza (range 1-8) at a dose of 100 mg/m(2) over 5 days following relapse. Eighteen patients (82%) also received a median number of two donor lymphocyte infusions (DLI, range 1-5). Sixteen patients (72%) responded to 5-Aza treatment and five patients (23%) achieved a CR. 5-Aza-induced CR lasted for 433 days (median, range 114-769). Median survival and the estimated 2-year survival rate were 144 days and 23%, respectively. Acute GVHD after DLI was seen in six patients (33%) and four of these patients developed chronic GVHD of the skin. There were no treatment-related deaths. Patients who achieved halving of leukocyte counts after the first 5-Aza cycle had a superior median survival of 802 days compared with 135 days (P=0.0025) in all other patients. On univariate analysis, the achievement of this halving of leukocyte counts was identified as a significant predictor of survival.
Asunto(s)
Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre/efectos adversos , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Terapia Recuperativa , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
In this prospective study, we examined the toxicity and efficacy of an intensified conditioning regimen for treatment of patients with relapsed or high-risk acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation. Fifteen patients received fludarabine 30 mg/m(2), cytarabine 2000 mg/m(2), amsacrine 100 mg/m(2) on days -10, -9, -8 and -7, anti-thymocyte globulin (ATG-Fresenius) 20 mg/kg body weight on days -6, -5 and -4 and fractionated total body irradiation 2 x 2 Gy on days -3, -2 and -1 (FLAMSA-ATG-TBI) before allogeneic hematopoietic stem cell transplantation. At the time of hematopoietic stem cell transplantation, 10 patients were in complete remission (8 CR1; 2 CR2), 3 with primary refractory and 2 suffered from refractory relapse. All patients achieved a complete remission after hematopoietic stem cell transplantation; and after a median follow-up time of 1091 days (range, 334-1554 days), nine patients (60%) are alive and free from disease, including three patients with prior refractory disease. Three patients died due to treatment-related mortality. The most frequent and severe conditioning-related toxicities observed in 9 out of 15 patients were grade III/IV infections according to common toxicity criteria. Thus, conditioning with the FLAMSA-ATG-TBI regimen is a feasible and effective alternative for patients with relapsed or high-risk acute lymphoblastic leukemia.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Amsacrina/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Recurrencia , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Irradiación Corporal Total/métodosRESUMEN
To date, G-CSF is the most favoured cytokine administered for PBSC mobilization because of its great efficacy and lack of serious toxicity. Recently, a pegylated filgrastim (pegfilgrastim) has been introduced. Attachment of the polyethylene glycol (PEG) moiety reduces renal excretion and masks proteolytic cleavage sites resulting in elevated G-CSF serum levels for up to 14 days after a single injection. As single-dose pegfilgrastim had similar effects in the prophylaxis of chemotherapy-induced neutropenia as the daily administration of the unconjugated drug, its capability for the mobilization of haematopoietic stem and progenitor cells has been assessed and presented to be at least equal to that of conventional G-CSF. Administration of pegfilgrastim following high-dose therapy and autologous blood SCT (BSCT) shortened the time to myeloid recovery as seen in conventional G-CSF. Plasma G-CSF levels were about 1 log higher with pegfilgrastim, but in the setting of autologous BSCT this did not translate into a faster haematopoietic recovery. Only few data exist on the biological effects of pegfilgrastim. Still, these data suggest that pegfilgrastim-stimulation results in different functional properties of haematopoietic stem and progenitor cells compared with G-CSF.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Filgrastim , Hematopoyesis/efectos de los fármacos , Humanos , Cinética , Polietilenglicoles , Proteínas Recombinantes , Trasplante AutólogoRESUMEN
The fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) can be found in about one quarter of patients with acute myeloid leukemia (AML) [Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematology. Educ. Program 2006;178-84 [Review]]. Patients who carry this mutation have a high risk of relapse even after allogeneic stem cell transplantation [Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J 2003;4:41-6; Meshinchi S, Arceci RJ, Sanders JE, Smith FO, Woods WB, Radich JP, et al. Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood 2006;108(1):400-1]. Recent reports show that Sorafenib, a multikinase inhibitor has significant activity against FLT3-ITD(+) blasts in vitro [Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y, et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007;21(3):439-45]. We here report the first clinical case of molecular remission induced by Sorafenib in a patient with FLT3-ITD(+) AML and extramedullary disease after allogenic stem cell transplantation.
Asunto(s)
Bencenosulfonatos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Piridinas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Humanos , Leucemia Mieloide Aguda/genética , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inducción de Remisión/métodos , Sorafenib , Secuencias Repetidas en TándemRESUMEN
The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC) and their resistance to classical therapies make it a prime candidate for adoptive immunotherapy. Highly potent antigen-presenting cells, namely dendritic cells (DCs), may serve as an interesting tool for anticancer vaccination. Here we report on the IN VITRO findings of a vaccination trial in five MTC patients, who were treated with a new DC generation protocol consisting of granulocyte-macrophage colony-stimulating factor and interferon-alpha (IFN-DCs). These cells were pulsed with tumor-specific calcitonin and administered twice. In two patients who responded to therapy we found a large increase (in mean 2.9+/-1.9%) of antigen-specific IFN-gamma-secreting CD4+ cells as well as an increase of granzyme B positive CD8+ cells (mean 2.2+/-0.2%) in the peripheral blood. In parallel, a decrease of CD4+/CD25+/FoxP3+ regulatory T cells was seen. Importantly, IN VITRO stimulation of PBMC with 10 different 15mer calcitonin peptides resulted in the identification of two HLA class II epitope regions within the central part of full-length calcitonin. These data were in accordance with the results drawn from the computer-based algorithm epitope prediction software SYFPEITHI. Measurement of different pro- and anti-angiogenic factors did not allow for a distinct outcome of prediction of the treated patients. In summary, we have demonstrated that immunization with IFN-DCs leads to a tumor epitope-specific immune response in MTC patients and may, therefore, represent a promising tool for future vaccination trials.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Carcinoma Medular/inmunología , Células Dendríticas/inmunología , Células TH1/inmunología , Neoplasias de la Tiroides/inmunología , Secuencia de Aminoácidos , Inductores de la Angiogénesis/sangre , Inductores de la Angiogénesis/metabolismo , Calcitonina/síntesis química , Calcitonina/inmunología , Calcitonina/uso terapéutico , Vacunas contra el Cáncer/síntesis química , Vacunas contra el Cáncer/inmunología , Carcinoma Medular/terapia , Separación Celular , Células Dendríticas/trasplante , Mapeo Epitopo , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Inmunoterapia Adoptiva , Interferón-alfa/inmunología , Datos de Secuencia Molecular , Linfocitos T/citología , Linfocitos T/inmunología , Neoplasias de la Tiroides/terapia , Vacunas de Subunidad/síntesis química , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/uso terapéuticoRESUMEN
The antitumor effects of IFNalpha is mainly mediated by the activation of cytotoxic T lymphocytes (CTLs), the activation of natural killer (NK) cells, and the generation of highly potent antigen-presenting dendritic cells (IFN-DCs). Recently, we demonstrated that these cells partially express the NK cell marker CD56 and reveal a direct cytotoxic immunity towards tumor cells. The aim of the present study was to explore these cells in more detail with respect to their phenotypical and functional characteristics. Flowcytometric analyses revealed that a 5-day incubation time of CD14+ monocytes with IFNalpha results in a steady increase of CD56 surface expression of these cells from 25% (+/-2%) on day 1 up to 68% (+/-11%) on day 5. Interestingly, additional culturing of negatively selected CD56- IFN-DCs also resulted in a partial CD56 surface expression. By comparing both cell types in more detail we found a significant decrease of CD14 expression on CD56+ IFN-DCs (66+/-6%) compared to CD56- IFN-DCs (76+/-6%). On the basis of functional tests, CD56+ IFN-DCs revealed a slightly increased phagocytosis capacity compared to CD56- IFN-DCs as only 82% of CD56- IFN-DCs showed a positive intracytoplasmatic signal after 60 minutes coculturing with FITC-labeled albumin, whereas 91% of CD56+ IFN-DCs were positive. Moreover, CD56+ IFN-DCs revealed a stronger T cell stimulation capacity compared to CD56- IFN-DCs. These results together with our previously described data suggest that CD56+ IFN-DCs and CD56- IFN-DCs may represent one identical cell population with different maturation status rather than two separate cell entities. Because of their high stimulating capacity and their direct cytolytic effects these cells represent a new promising tool for cellular anticancer therapy.
Asunto(s)
Células Dendríticas/inmunología , Interferón-alfa/inmunología , Monocitos/inmunología , Biomarcadores/sangre , Antígeno CD56/inmunología , Antígeno CD56/metabolismo , Separación Celular , Técnicas de Cocultivo , Células Dendríticas/química , Células Dendríticas/citología , Citometría de Flujo/métodos , Humanos , Células Asesinas Naturales/citología , Activación de Linfocitos , Monocitos/citología , FagocitosisAsunto(s)
Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 4 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Translocación Genética , Adulto , Benzamidas , Humanos , Mesilato de Imatinib , MasculinoRESUMEN
In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adeno-associated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62-82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3-14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vector-mediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Genes p53/genética , Terapia Genética , Neoplasias Pulmonares/terapia , Inhibidores de Proteasas/uso terapéutico , Pirazinas/uso terapéutico , Apoptosis , Bortezomib , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Terapia Combinada , Docetaxel , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Guanina/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed , Inhibidores de Proteasoma , Taxoides/uso terapéutico , Transfección , Células Tumorales CultivadasAsunto(s)
Factor Estimulante de Colonias de Granulocitos/efectos adversos , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica , Rotura del Bazo/complicaciones , Rotura del Bazo/tratamiento farmacológico , Adulto , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Polietilenglicoles , Proteínas Recombinantes , Factores de Riesgo , Rotura Espontánea , Rotura del Bazo/diagnóstico , Trasplante Autólogo , Resultado del TratamientoRESUMEN
We report on two female patients who presented with painful recurrent palpable purpura, ulcers and necroses on the extremities. The results of all examinations and laboratory tests considered together suggested a diagnosis of necrotizing leukocytoclastic vasculitis. Leukocytoclastic vasculitis is an inflammatory necrotizing condition of the superficial dermal vessels, presenting with variable clinical symptoms. In most cases it becomes manifest as palpable purpura, but hemorrhagic-necrotizing, bullous, nodular and urticarial presentations also occur. Common etiological factors include bacterial, viral or drug antigens, chronic infections (hepatitis B and C), non-Hodgkin lymphomas (monoclonal gammopathy, multiple myeloma), leukemia (hairy cell leukemia), and tumors (bronchial, breast, and gastric cancer) and also connective tissue disorders. In the course of the work-up, a plasmocytoma was discovered as the cause of the leukocytoclastic vasculitis, presenting in a similar way to livedo reticularis in one case and to pyoderma gangraenosum in the other.
Asunto(s)
Plasmacitoma/complicaciones , Plasmacitoma/diagnóstico , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/diagnóstico , Vasculitis/diagnóstico , Vasculitis/etiología , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Raras/diagnóstico , Enfermedades Raras/etiologíaRESUMEN
We conducted a randomised trial comparing an intensified versus a standard conditioning regimen for high-dose chemotherapy followed by autologous stem-cell transplantation in patients with multiple myeloma. In this study, 56 patients were randomly assigned for high-dose therapy with melphalan 200 mg/m2 or with idarubicin 42 mg/m2, melphalan 200 mg/m2 and cyclophosphamide 120 mg/kg. The primary objective was response rate. Acute toxicity, mainly because of infections, was higher in the intensified treatment arm with a treatment-related mortality of 20% versus 0% in the standard arm. This lead to the early discontinuation of the study. Response rates did not differ significantly between both treatment arms {intensified versus standard: complete response+near complete remission 50% [95% confidence interval (CI) 26-74%] vs. 33% (95% CI 17-55%), partial remission 35% (95% CI 16-61%) vs. 50% (95% CI 30-70%)}. After a follow-up of 5 years, the median time-to-progression and overall survival were not significantly different between both patient groups. Analysis restricted to patients surviving the first 100 d after transplant showed a better outcome for patients with >or=2 bad prognostic risk factors in the intensified treatment arm, however all treatment-related deaths occurred within this group of patients. In conclusion, intensified conditioning for high-dose therapy had intolerably high toxicity without improving outcome in patients with multiple myeloma.